Westfeldt started her career as a New York-based theater actor, and has starred in over 25 Off-Broadway and regional productions. She first came to Hollywood in 1997.[7] That year, she co-wrote and starred in an Off-Broadway play with Heather Juergensen called Lipschtick: The Story of Two Women Seeking The Perfect Shade that caught the attention of Hollywood studios. It was optioned by Radar Pictures and made into Kissing Jessica Stein, in which Westfeldt and Juergensen starred.[7] Westfeldt is also well known for her most recent film, Friends with Kids, in which she starred, produced and made her directorial debut. She is also a veteran television actress and has held roles in a diverse selection of shows.

In 2001, Westfeldt appeared in her breakthrough role as Jessica in Kissing Jessica Stein. Fox Searchlight released it to critical acclaim in March 2002.[7] The film was an extended version of one of the sketches Westfeldt and Juergensen had written for Lipschtick.[8] For her role, Westfeldt won the Golden Satellite Award for Best Actress in A Comedy, an Indie Spirit nomination for Best First Screenplay with Juergensen, and a Special Jury Prize for Writing and Acting at the Los Angeles International Film Festival.[9] The film also won the Audience Award for Best Feature at the Los Angeles International Film Festival, the Audience Favorites Award at the Chicago International Film Festival, the Audience Award at the Miami Film Festival, Best Feature at the Louisville Jewish Film Festival, and the GLAAD Media Award.

Westfeldt was cast in a series regular role for Two Guys, a Girl and a Pizza Place alongside Ryan Reynolds, Traylor Howard and Richard Ruccolo during its first season on ABC in 1997. In 2001 she was featured in three episodes of Judging Amy. In 2007, Jennifer was cast as the lead of ABC's Notes from the Underbelly, directed and executive produced by Barry Sonnenfeld. Notes ran for two seasons on ABC. Her recent television credits include memorable arcs on ABC's hit Grey's Anatomy, as well as starring in the TV movie Before You Say I Do (2009) opposite David Sutcliffe.[10] Additional television credits include appearances in The Gene Pool, Dante, Hack, Snoops, and The Untitled New York Project.

In 2010, she was a guest star on Numb3rs for show 24 of the eighth season. She first appeared in the first four episodes of the season and returned in the final episodes of the series.[7]